This Program Project renewal focuses on Integrative Neurobiology of Cardiovascular Regulation. It has represented the major scientific emphasis of the Cardiovascular Research Center at Iowa since 1971. The strong cohesive interactions between senior basic scientists and clinical investigators is complemented by innovative directions with the recruitment of outstanding new scientists. The scope extends from work in cellular/molecular biology to integrative neuroscience; from gene transfer in cultured cells to genetically engineered animals; and from studies in isolated systems to mechanistic research in humans. There are five major Projects, each with tightly related interactive Parts. "Central RAS and Cardiovascular Regulation" defines the central action of angiotensin by selective targeting of central nuclei for gene transfer, regulation of gene expression, chemical ablation and cellular electrophysiology. "Modulation of Sensory Inputs by CGRP" is a coordinated effort to explore the activation of trigeminal afferents by nociceptive stimuli and subarachnoid hemorrhage (SAH). Changes in the expression of CGRP may mediate the disabling autonomic responses to pain and the devastating vasospasm in SAH, and hold the promise of therapeutic gene transfer. In "Leptin and Central Autonomic Drive" the focus is on the effect of leptin, at the level of hypothalamus, in transducing the activation of sympathetic pathways. The availability of genetic models of obesity and the convergence of diverse scientific expertise, provide a unique opportunity to clarify the autonomic-leptin interaction, and to extend the work to obese humans. Our experience in the mechanisms of baroceptor activation and new interests in the biology and biophysics of ion channels will be merged on "Cellular/Molecular Mechanism of Mechanosensation and Excitation of Baroreceptor Neurons." Four separate but interrelated Parts will pursue the concepts that ENaC/degenerin family members are the BR sensors, and that methionine oxidation-reduction is important in the regulation of BR ion channels by autocrine factors. These are novel and important concepts. "Nitrosyl Factors and Neurovascular Control" Extends ongoing work on the interaction between glutamatergic and nitroxidergic neurons in the NTS, which influences the central mediation of the baroreflex often impaired in hypertension and aging. A second Part addresses the novel hypothesis that "preformed stores"of nitrosyl factors, at the neuro-endothelial-vascular interface, represent a major mechanism of regulation of vascular tone. Essential Core functions will support these projects in the areas of "Imaging," "Transgenic Animals," and "Vector-Mediated Gene Transfer." The tract record of productivity, creative interactions, innovative concepts and state-of-the-art approaches promise the optimal realization of the work whereby the scientific outcome will be far greater than the sum of the components.